Many types of cells undergo apoptosis as part of the normal physiological
process. An interruption in apoptosis is thought to be a primary cause
of tumor growth. Two presentations concerning this subject were made at
the 88th Annual Meeting of the American Association for Cancer Research
In the first presentation, Stanley J. Korsmeyer, MD, of the Howard Hughes
Medical Institute at Washington University School of Medicine in St. Louis,
discussed a series of genes, B-cell lymphoma 2 (bcl-2), bax,
bad, and abid, that regulate cell death. The bcl-2 protein
has the novel function of blocking programmed cell death, extending the
survival of cells normally destined to die. For example, mice that over-express
bcl-2 progress to life-threatening lymphoma. According to Korsmeyer,
bcl-2 does not act alone but duels with its counteracting twin,
bax. When bax is in excess, cells execute the programed death command.
However, when bcl-2 dominates, the process is interrupted and cells
In studies of bcl-2-deficient mice, Dr. Korsmeyer found that
the embryos developed normally. However, when the mice reached adulthood,
bax predominated, leading to massive cell death of lymphocytes and
the disappearance of lymphoid organs. In addition, the embryonic loss of
kidney cells led to polycystic kidney disease, and the death of melanocytes
caused hair hypopigmentation. When Dr. Korsmeyer studied bax-deficient
mice, he found that bcl-2 predominated. These mice displayed cellular
hyperplasia and aberrations in cell death during the development of the
According to Dr. Korsmeyer, "bcl-2 represents an important
control step in the common pathway of apoptosis present in all cells. Evidence
indicating that it serves as a critical checkpoint includes its role in
the generation of human disease, its importance in developmental cell death,
and its selection as a site of interference by DNA viruses. Further study
of the bcl-2 family holds the promise of improving our understanding
of the pathway of programmed cell death and the aberrations in this process
that result in malignancy."
A Second Study
In another study, Huachen Wei, MD, PhD, Associate Professor of Dermatology
at the Mount Sinai School of Medicine in New York, and his colleagues evaluated
methods of regulating apoptosis as a new approach to the understanding
of ultraviolet-induced carcinogenesis. They hypothesized that apoptosis
could be induced by stimulating the tumor suppressor gene p53 or
by down-regulating the expression of the apoptosis suppressor gene bcl-2.
The p53 gene is thought to suppress tumor growth through two mechanisms:
by arresting cell growth at a specific phase in the cell cycle and by inducing
apoptosis. Mutations in this gene are thought to be the most common genetic
mutations in human cancers.
Using a cell line that expresses both p53 and bcl-2, the
investigators found that ultraviolet B radiation (UVB) significantly induced
the expression of p53 in a dose- and time-dependent manner. However,
exposure to the equally cytotoxic dose of ultraviolet A radiation (UVA)
produced no effects on p53 expression. On the other hand, UVA substantially
down-regulated the expression of bcl-2, whereas exposure to the
same level of UVB produced no change in the expression of bcl-2.
"Our results indicate that both UVA and UVB cause cell damage and
induce apoptosis by completely separate mechanisms," said Dr. Wei.
"Because mutations in p53 and over-expression of bcl-2
can result in human cancers, our findings suggest that ultraviolet radiation
may provide a new approach for drug development," said Dr. Wei.